Abstract 11395: Small Molecule Antidote for Anticoagulants
New generation oral factor Xa and IIa inhibitors offer significant advantages over heparins and warfarin with regards to route of administration, drug interactions and predictability of bioactivity. Yet, unlike warfarin and unfractionated heparin, oral factor Xa and IIa inhibitors lack reversal agents. Therefore, concern over serious and fatal bleeds caused by oral factor Xa and IIa inhibitors is heightened. We set out to rationally design, synthesize, and characterize a synthetic small molecule anticoagulant antidote. Plasma was separated by centrifugation from whole blood drawn from healthy human volunteers, collected, and spiked with rivaroxaban or apixaban at 1x and 2x the therapeutic Cmax. Anticoagulation was then reversed with Perosphere’s new anticoagulant antidote PER977. Factor Xa activity was measured before and after reversal using an FDA 510(k)-cleared chromogenic anti-Xa kit (Hyphen-BioMed, France). PER977 completely reversed the anti-Xa activity of rivaroxaban (see figure) and apixaban in a dose-dependent fashion ex vivo in human plasma. Additionally, weight-matched rats were overdosed with rivaroxaban, apixaban, or dabigatran as confirmed by large increases in blood loss volume. They were then administered either a sham dose or PER977. After thirty minutes, blood loss volume was quantified. PER977 demonstrated complete reversal of rivaroxaban and apixaban in human plasma. Additionally, no pro-coagulant effects were observed. PER977 decreased bleeding by >90% in vivo in rats treated with rivaroxaban, apixaban, and dabigatran, reducing it to within the normal range for un-anticoagulated rats in a standard tail transection bleeding model. As with the human plasma study, no pro-coagulant effects were observed. In conclusion, PER977 is a synthetic small molecule new chemical entity under development that reverses new generation oral anticoagulants ex vivo in human blood and decreases bleeding in vivo in a standard rat tail bleeding model.
- © 2012 by American Heart Association, Inc.